UVA-1 cold light therapy in the treatment of at by gdw87570

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									                          Chapter 2




   1 od i g          n             t f pi
UVA- c l l ht therapyi the treatmen o ato c

   d     ti: 1    en         n       d
    ermati s 6 pati tstreatedi the Lei en

              iersty   ial ter
            Un v i M ed c Cen


      M.C.A. Polderman, M. Wintzen, S. le Cessie, S. Pavel




     Photodermatol Ph       nol otomed 2 0 ;19 - 6
                     otoimmu Ph         0 52 :3 9
Chapter 2


Abstract



   k round: UVA-1 has b shown to b efec in the treatment ofpatients with atopic
Bac g                  een        e f tive

dermatitis. However, its optimal therapeuticc                   et ully
                                             onditions are not y f established.

         n
Methods: I an open prospective study we retrospectively c              f t
                                                         ompared the efec of4weeks

        32                   f t                   s        29
therapy ( patients)with the efec ofthe usual 3 week therapy ( patients)in patients

with atopicdermatitis, usinga medium dose UVA-1 c lig ( 5 Jc 2) 5 day a week
                                                 old ht 4 /m ,       s      .

Results: Sc                              SCORAD) and dermatolog lif q
           oring atopic dermatitis index (                     y e uality index

DLQI q
(               e      es           nif antly during b 3 and 4week UVA-1.
   ) uality oflif index improved sig ic               oth         s

                          or     s
Patients who were treated f 4week showed a superior improvement ofthe SCORAD index

23.12 points, 95% c idenc interval ( )16.09-30.16, vs. 13.32 points, 95% CI5.61-
(                  onf   e         CI

     ,         ,             5.4                   -7 8         6
21.04 p = 0.059) and the DLQI( 1 points, 95% CI2.38 .8 , vs. 3.8 points, 95% CI

   8 4              , ompared with patients who were treated f 3 week However, the
1.8 -5.8 , p = 0.360) c                                      or      s.

   f    es           h         al nif anc                               or
diferenc did not reac statistic sig ic e. Onlypatients who were treated f 4weeks

       le                                   s ter      . n oth g
were ab to maintain their improvement 6 week af therapy I b     roups 50% of

                                          al ortic
patients had intermittentlyused mild topic c                       ollow-up period.
                                                  osteroids in the f

Conclusion: Ex                        rom 3 to 4week results in a c ally relevant
              tension ofUVA-1 therapy f             s              linic

improvement of the outc                     ed             f ts,        y
                       ome, and more prolong therapeutic efec measured b the

SCORAD index.




36
Introduction



Since the 1970s psoralens and ultraviolet A radiation (PUVA) therapy has been successfully

used for the treatment of atopic dermatitis. Alternative forms of phototherapy for the same

disease have been UVB, narrow-band UVB and UVA-UVB combination therapy. In the

1980s UVA-1 treatment was introduced. This long-wave (340-400 nm) UVA treatment

appeared to be a promising phototherapeutic modality. Some authors have reported on good

results of high-dose (130 J/cm2, 3 weeks) UVA-1 in the treatment of atopic dermatitis,1

whereas others have shown that also medium doses of UVA-1 (50 J/cm2, 3 weeks) could be

successfully applied.2 In several controlled trials, both high- and medium-dose UVA-1

proved to be more effective than UVA-UVB combination therapy.1-4

              ig.
We observed (F 2.1.), together with some other authors that after a successful 3 weeks of

medium dose UVA-1 therapy, eczema deteriorated relatively soon.5 To investigate if the

prolongation of treatment leads to a longer therapeutic response we treated 61 patients with

atopic dermatitis with medium-dose UVA-1 during either 3 or 4 weeks, and we evaluated

disease activity, quality of life and duration of improvement after a follow-up period of

6 weeks.



Patients and methods



In an open prospective study 32 patients with atopic dermatitis were treated with UVA-1

during 4 weeks. Their therapeutic effect was retrospectively compared with the effect of

UVA-1 in 29 patients who were treated during the usual 3 weeks. The mean age of patients

                                                                  ority of the patients had
was 33.4 years (range 17-73), 19 were male, 42 were female. The maj

skin type II (24/61), or III (29/61). The remaining eight patients had skin type I (4/61) or V


                                                                                           37
Chapter 2


                                                          Scoring atopic dermatitis index
(4/61) Patients with moderate to severe atopic dermatitis [

(SCORAD) range 14.8-76.2]with insufficient effect of local corticosteroids, and no use of

systemic corticosteroids or cyclosporine therapy in the previous 2 months, were included.

A Photomed 250 000 unit (BioSun Sylt Service GmbH, www.biosunsylt.com), emitting

photons with wave-lengths of 340-500 nm, with an irradiance of 31 mW/cm2, was used.

Owing to a filter system that eliminates all infrared (i.e. heat producing) radiation and a

ventilation system providing a cool breeze, this UVA-1 therapy is also called UVA-1

cold-light therapy.

Patients were treated with 45 J/cm2, 5 days a week, during 3 (29 patients) or 4 (32 patients)

weeks. In the first week, the UVA-1 dose was increased from 3 J/cm2 on Monday to 15 J/cm2

on Tuesday, and further increased by 10 J/cm2 every day to a maximum of 45 J/cm2 on

Friday. The cumulative UVA-1 doses were 573 and 798 J/cm2 for the 3 and 4 weeks

treatment schedule, respectively. During therapy patients wore goggles. Before the treatment,

weekly during treatment, and 3 weeks and 6 weeks after treatment, two scoring systems were
                                                         6
applied: the SCORAD (maximum possible score 103)             and the Dermatology Life Quality

Index (DLQI, maximum possible score 30 = maximal discomfort).6,7 The examination of both

scoring systems was performed by the same investigator who evaluated these parameters also

in the 3 weeks’treated patients.

Except for the first week during which the daily dose was gradually increased to 45 J/cm2,

patients used no topical steroids or antihistamines until the follow-up. Emollients could be

used infinitely until 3 h before irradiation to prevent glimmering of the skin and consequent

radiation reflection. Temperature on the skin surface was measured after 10 min to compare

with heat producing qualities of PUVA units reported in literature.8

A paired t-test was used to assess changes in the SCORAD index, and the DLQI during and

after treatment. A non-paired t-test was used to compare mean changes between the 3 and 4


38
weeks treatment regimen. Analyses were performed according to the intention to treat

principle. Statistical significance was defined as p 0.05.



Results



UVA-1 treatment resulted in a statistically significant decrease of the SCORAD index at the

end of therapy [18.5 points, p = 0.0001, 95% confidence interval (CI) 13.26-23.67]. Baseline

SCORAD (p = 0.75) and DLQI (p = 0.59) indexes of the 3 weeks’ treated patients did not

differ from those of 4 weeks’ treated patients. The patients who had been treated for 4 weeks

achieved better results (mean decrease of 23.12, SD = 19.52 , p < 0.001, 95% CI 16.09-30.16)

than those treated for 3 weeks (mean decrease of 13.32 points, SD = 20.28, p = 0.001,

95% CI 5.61-21.04) (Fig. 2.1.). However, this difference was just not statistically significant

(p = 0.059, 95% CI –20.00-0.40). Furthermore, when both groups had been treated for

3 weeks, the difference in improvement of the SCORAD index was not statistically

significant (p = 0.256). After a 6 weeks’ follow-up period 50% of patients were lost to

follow-up in both groups. These patients had not responded better or worse to UVA-1 therapy

than the patients who were not lost to follow-up. At that moment in time the SCORAD index

of patients in both groups had increased by five points, which corresponded to a 21.6% loss

of post-treatment effect for the 4 weeks’ treated group and a 37.5% loss of post-treatment

effect for the patients who were treated for 3 weeks. The patients from the 4 weeks treatment

regimen still showed a significant improvement of their SCORAD index compared with

pretreatment values, whereas those who were treated during 3 weeks did not (Fig. 2.1.).

In both groups approximately 50% of patients had intermittently used mild topical

corticosteroids during the follow-up period. The patients who did not need topical

corticosteroids during follow-up had not responded better or worse to UVA-1 therapy than


                                                                                            39
Chapter 2


the patients who did use local corticosteroids during follow-up. The DLQI showed a

significant decrease after both 3 (3.86 points, SD = 5.20, p<0.000, 95% CI 1.88-5.84) and

4 weeks (5.41 points, SD = 7.53, p = 0.001, 95% CI 2.38-7.88) of UVA-1 therapy. The effect

of two treatment regimens did not differ significantly (p = 0.360, 95% CI –1.81-4.90). Similar

to the SCORAD index, only patients who had been treated for 4 weeks were still significantly

improved at 6 weeks after therapy (Fig. 2.2.).

UVA-1 cold light therapy was generally well tolerated by patients. During treatment the

                                            C
maximum temperature at body distance was 34° (range 24-34°C). In PUVA-cabins

temperatures up to 41° were reported.8 Some side-effects occurred. Fifteen (24.6%) patients
                      C

experienced slight erythema in the first week that did not require any treatment and resolved

spontaneously in a few days. This could be explained by the relatively light skin type of these

patients (2/15 skin type I, 11/15 skin type II, 2/15 skin type III). Eight patients (13.1%)

dropped-out: Two of them developed a photosensitive reaction (one had solar urticaria, the

other probably had a light phototoxic reaction because of cosmetics), six others exacerbated

after 1 (n= 2) and 2 weeks (n= 4). Their inferior therapeutic results might explain the large

standard deviations of both SCORAD and DLQI improvements.




40
Discussion



With the use of medium doses of UVA-1 a mean improvement of SCORAD indices of 38%

after 3 weeks was comparable with the results reported in literature.9-11 A four weeks’

treatment regimen appeared to result in a better outcome immediately after therapy than the

3 weeks’ regimen. Although not statistically significant, the authors find the difference

clinically relevant. Furthermore, compared with the 3 weeks’ regimen, the maintenance of

achieved clinical results during follow-up was improved. The 1-week extension of therapy

might thus partly overcome the problem of deterioration of eczema after three weeks of

medium dose UVA-1 as also reported by others.5 However, as both groups deteriorated

five points during the 6 weeks’ follow-up period, the authors realize that the improved

maintenance of therapeutic results in the 4 weeks’ treated group is partly explained by the

superior improvement of the SCORAD and DLQI indexes immediately after therapy in the

4 weeks’ treated group. The question remains whether the demanding treatment schedule,

i.e. 5 days a week, is necessary and whether less frequent irradiations (2-3 /week) would have

similar therapeutic effects.

PUVA therapy is a frequently used form of phototherapy in the treatment of atopic dermatitis.

So far, there have been no studies published comparing the efficacy of UVA-1 with PUVA in

the treatment of atopic eczema. Photosensitivity caused by psoralens requires protection of

the eyes and the skin against sunlight during the rest of the day. Furthermore, up to 20% of

patients suffer from side-effects of oral psoralens.12 In our study, apart from some slight

erythema in the first week and a photosensitive reaction in two patients, no short-term

side-effects were seen.




                                                                                           41
Chapter 2



                                              s   1
                                        3 week UVA-           s   1
                                                        4 week UVA-

                  70
                  60
                                   *
                  50                                                                        *
        SCORAD




                                                                          **       **
                  40
                  30
                  20
                  10
                   0
                       0   1   2    3    3    6     0     1   2       3   4         3    6
                                          t    t
                                        afer afer                                    t    t
                                                                                   afer afer
                                                weeks



Figure 2.1. Mean Scoring atopic dermatitis index (SCORAD) ± standard deviation during 3

and 4 weeks UVA 1 and follow-up. 3 after/6 after: 3 and 6 weeks after UVA-1 therapy,

 p=       *
* 0.001, * p 0.001.




                                              s   1
                                        3 week UVA-           s   1
                                                        4 week UVA-

                 20

                 15                                                                     #       ##
                                   **                                          *
     DLQI




                 10

                  5

                  0
                       0   1   2   3     3    6     0     1    2      3    4         3    6
                                          t    t
                                        afer afer                                     t   t
                                                                                    afer afer
                                                weeks


Figure 2.2. Mean dermatology life quality index (DLQI) ± standard deviation during 3 and

4 weeks UVA-1 and follow-up. 3 after/6 after: 3 and 6 weeks after UVA-1 therapy,

 p          *          p          #
* = 0.001, * p 0.001, # = 0.015, # p = 0.026.




42
PUVA and UVA-1 have different cellular targets. In PUVA therapy, psoralens bind to DNA

molecules, followed by a UVA-induced photochemical reaction that is taking place in close

vicinity of DNA molecules. Consequently, it is not surprising that long-term repetitive PUVA

results in an increased risk of skin cancer.13,14 UVA-1 photons are not absorbed by nucleic

acids. The most important targets of UVA-1 radiation are located in the mitochondria that

contain relatively large concentrations of UVA-1 absorbing co-enzymes of the redox chain.

DNA damage is mediated indirectly by the production of radical oxygen species. Although

animal studies suggest that UVA-1 is less carcinogenic than UVA-2 and UVB,15 the

long-term carcinogenic hazards of UVA-1 remain to be clarified and should not be

underestimated. Some authors also showed that UVA-1 is capable of inducing squamous cell

carcinoma in mice.16,17 This radiation can induce expression of p53 and pyrimidine dimers in

human skin and in murine skin, however much less effectively than UVB and solar simulated

radiation.18-20 It is not yet clear whether UVA-1 plays a role in the etiology of melanoma.

A recent experimental work has brought some evidence that UVB, but not UVA irradiation

initiated melanoma in transgenic mice.21

UVA-1 radiation has been shown to generate singlet oxygen and superoxide anions.22,23

Extensive production of such reactive oxygen species can, apart from contributing to

carcinogenity, in certain cell types, lead to apoptotic death.24 Lymphoid cells have frequently

been used for the investigation of UVA-mediated apoptotic responses because of their lower

threshold for switching to the UV-induced apoptotic program.22,25 At least part of the

therapeutic response to UVA-1 radiation could thus be ascribed to an apoptosis-inducing

effect on the inflammatory infiltrate and especially on T-helper cells.23,26

Our work supports the earlier studies of others showing that UVA-1 therapy can be

successfully used as a monotherapy in the treatment of atopic dermatitis. For the prolongation

of its therapeutic effects, a 4 weeks’ treatment regimen is preferable to a 3 weeks’ regimen.


                                                                                            43
Chapter 2


Still , the place of UVA-1 in the treatment of atopic dermatitis needs to be better defined, e.g.

by a multicenter comparative trial with other photo(chemo)therapeutic modalities.



Acknowledgements



We thank the nursing personnel for carrying out the greatest part of the daily irradiations.




44
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